Bisphenol A Induces Gene Expression Changes and Proliferative Effects through GPER in Breast Cancer Cells and Cancer-Associated Fibroblasts

Department of Pharmaco-Biology, University of Calabria, Rende, Italy.
Environmental Health Perspectives (Impact Factor: 7.98). 05/2012; 120(8):1177-82. DOI: 10.1289/ehp.1104526
Source: PubMed


Background: Bisphenol A (BPA) is the principal constituent of baby bottles, reusable water bottles, metal cans, and plastic food containers. BPA exerts estrogen-like activity by interacting with the classical estrogen receptors (ERα and ERβ) and through the G protein-coupled receptor (GPR30/GPER). In this regard, recent studies have shown that GPER was involved in the proliferative effects induced by BPA in both normal and tumor cells.
Objectives: We studied the transduction signaling pathways through which BPA influences cell proliferation and migration in human breast cancer cells and cancer-associated fibroblasts (CAFs).
Methods and results: We used as a model system SKBR3 breast cancer cells and CAFs that lack the classical ERs. Specific pharmacological inhibitors and gene-silencing procedures were used to show that BPA induces the expression of the GPER target genes c-FOS, EGR-1, and CTGF through the GPER/EGFR/ERK transduction pathway in SKBR3 breast cancer cells and CAFs. Moreover, we observed that GPER is required for growth effects and migration stimulated by BPA in both cell types.
Conclusions: Results indicate that GPER is involved in the biological action elicited by BPA in breast cancer cells and CAFs. Hence, GPER-mediated signaling should be included among the transduction mechanisms through which BPA may stimulate cancer progression.

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    • "BPA has been detected in the human placenta (Schonfelder et al., 2002), cord blood (Wan et al., 2010), amitotic fluid (Ikezuki et al., 2002; Yamada et al., 2002), fetal liver (Cao et al., 2012) and breast milk (Sun et al., 2004), making exposure of human neonates and infants a very real concern. According to studies, BPA is estrogen mimic compound resulted in an array of health impacts including prostate and breast cancer (Prins et al., 2008; Pupo et al., 2012). The adverse effects of BPA are largely related to its estrogenic activity (Hiroi et al., 1999; Kurosawa et al., 2002). "
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    • "In recent years, receptor-mediated and cell signaling-mediated mechanisms have gained considerable concern and gradually became the main theory to interpret the HCR at molecular level (Calabrese, 2013b). For instance, the BPA-induced cell proliferation at low concentration results from a feedback stimulatory loop by activating the G protein-coupled receptor (GPCRs)-mediated signaling pathway (Bouskine et al., 2009; Pupo et al., 2012; Sheng et al., 2013). The receptor-mediated hormetic mechanism can be divided into three modes: (Calabrese, 2013b) 1. "
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    Chemosphere 03/2015; 132:108-113. DOI:10.1016/j.chemosphere.2015.03.030 · 3.34 Impact Factor
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    • "There is very limited published data about effects of eDcs on the metastasis of colorectal cancer. It has been reported that BPA can induce migration of breast cancer—associated fibroblasts (cAFs) and conditioned medium from BPA-treated cAFs can induce migration of SKBr3 cells (Pupo et al. 2012). "
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